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WO2013106847A1 - Composés, compositions et procédés associés comprenant des 3-aryl-quinoléines - Google Patents

Composés, compositions et procédés associés comprenant des 3-aryl-quinoléines Download PDF

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Publication number
WO2013106847A1
WO2013106847A1 PCT/US2013/021472 US2013021472W WO2013106847A1 WO 2013106847 A1 WO2013106847 A1 WO 2013106847A1 US 2013021472 W US2013021472 W US 2013021472W WO 2013106847 A1 WO2013106847 A1 WO 2013106847A1
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WIPO (PCT)
Prior art keywords
compound
compounds
aryl
ether
substituted
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PCT/US2013/021472
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English (en)
Inventor
Michael K. Riscoe
Rolf W. Winter
Sovitj Pou
David J. Hinrichs
Jane Xu KELLY
Yuexin LI
Aaron Nilsen
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Oregon Health & Science University
The United States Government As Represented By The Department Of Veterans Affairs
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Application filed by Oregon Health & Science University, The United States Government As Represented By The Department Of Veterans Affairs filed Critical Oregon Health & Science University
Priority to US14/371,870 priority Critical patent/US9249103B2/en
Priority to EP13735565.7A priority patent/EP2802565A4/fr
Publication of WO2013106847A1 publication Critical patent/WO2013106847A1/fr
Priority to US14/977,271 priority patent/US20160340313A1/en
Priority to US15/440,458 priority patent/US10023538B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • alkoxy refers to an alkyl group attached to an oxygen atom to form an ether.
  • the alkoxy group may be a "substituted alkoxy" wherein one or more hydrogen atoms are substituted with a substituent such as halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, or carboxyl.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ether, ketone, aldehyde, hydroxy, carboxylic acid, cyano, amido, haloalkyl, haloalkoxy, or alkoxy, or the aryl group can be unsubstituted.
  • Heterocycle means any optionally substituted saturated, unsaturated or aromatic cyclic moiety wherein said cyclic moiety contains at least one heteroatom selected from at least one of oxygen (O), sulfur (S), phosphorus (P) or nitrogen (N). Heterocycles may be monocyclic or polycyclic rings.
  • Optionally substituted alkyl groups include haloalkyl groups, such as fluoroalkyl groups, including, without limitation, trifluoromethyl groups, trifluoromethyl ethers, and 1 ,1 ,1 -triflouoroethyl ethers.
  • fluoroalkyl groups including, without limitation, trifluoromethyl groups, trifluoromethyl ethers, and 1 ,1 ,1 -triflouoroethyl ethers.
  • salts may be prepared by standard procedures, for example by reaction of the free acid with a suitable organic or inorganic base. Any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof.
  • Ri is a substituted alkyl and Xi , X2, X3, X4, and X 5 are independently selected from at least one of H, halo, alkoxy, ether, alkyl, substituted alkyl, alkyl ether, haloalkyi, haloalkyi ether, aryl, substituted aryl, aryl ether, substituted aryl ether, aryl amine, 5-member heterocycle, 6-member heterocycle, amino, benzylic amide, alkoxy, cyano, morpholinyl, N-ethyl morpholinyl, or carboxyl.
  • n is an integer equal to 2 or 3.
  • X2, X3, and X4 are independently H, halo, halomethyl, halomethoxy, dihalomethoxy, trihalomethoxy, haloethoxy, 1 ,1 ,1 - trihaloethoxy, phenyl, phenyl ether, halomethoxy substituted phenyl, halomethoxy substituted phenyl ether, trihalomethoxy substituted phenyl ether, dimethylamino, cyano, morpholinyl, or ethyl-N-morpholine.
  • Examples of compounds of formula (III) include
  • prodrug also is intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when the prodrug is administered to a subject.
  • the compounds and compositions disclosed herein may be delivered in prodrug form.
  • prodrugs of the presently disclosed compounds methods of delivering prodrugs and compositions containing such prodrugs.
  • Prodrugs of the disclosed compounds may be prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound.
  • Prodrugs include compounds having a phosphonate and/or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino and/or phosphonate group, respectively.
  • Examples of prodrugs include, without limitation, compounds having an acylated amino group and/or a phosphonate ester or phosphonate amide group.
  • a prodrug may be a lower alkyl phosphonate ester, such as a methyleno phosphonate ester or an isopropyl phosphonate ester.
  • Protected derivatives of the disclosed compounds also are contemplated.
  • a variety of suitable protecting groups for use with the disclosed compounds are described.
  • Other conventional protecting groups can be selected by those of skill in the art, and/or in consultation with Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.
  • protecting groups are removed under conditions which will not affect the remaining portion of the molecule.
  • These methods include, for example, acid hydrolysis and hydrogenolysis.
  • One exemplary method involves the removal of an ester moiety, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate.
  • a second exemplary method of removing a protecting group involves removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol or acetic acid, or mixtures thereof.
  • a t-butoxy- based group, including a t-butoxycarbonyl protecting group may be removed utilizing an inorganic or organic acid, such as HCI or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride.
  • Another exemplary protecting group suitable for protecting amino and hydroxyl functions, is trityl.
  • an amine is deprotected, the resulting salt can readily be neutralized to yield the free amine.
  • an acid moiety such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof.
  • Embodiments of the compounds disclosed herein include one or more asymmetric centers; thus, these compounds may exist in different stereoisomeric forms. Accordingly, compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures. In certain embodiments, the compounds disclosed herein may be synthesized in or are purified to be in a substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form.
  • the compounds described herein may be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • compounds according to the present description can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., i H or 13C NMR), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatograpy
  • Scheme 1 One embodiment of a scheme for the synthesis of Compound 1 is shown herein as Scheme 1 .
  • Scheme 1 may be readily applied to the synthesis of other 3- aryl quinolines, as recognized by those skilled in the art.
  • the first step involves the selective iodination of position 3 of the quinolone nucleus with iodine in the presence of n-butylamine in DMF to give 7-chloro-3- iodoquinolin-4-ol (B) according to the procedure of Hart (Hart, J Med Chem 49, 1 101 -1 1 12 (2006) incorporated by reference herein), in approximately 59% yield. Without further purification, this material is converted cleanly to the corresponding 4,7-dichloro-3-iodoquinoline (C) in approximately 99% yield according to the procedure of Andersag (Andersag, Chem Ber 81 , 499-507, (1948), incorporated by reference herein).
  • the iodoquinoline is then treated in THF with potassium ethoxide in the presence of a catalytic amount of 18-crown-6 ether to give pure 7-chloro-4- ethoxy-3-iodoquinoline (D) in approximately 90% yield as shown, for example, by GC-MS and NMR.
  • Suzuki coupling conditions (Mphahlele, J Chem Res 2008, 437-440 (2008) incorporated by reference herein) may be used to react 4- (trifluoromethoxy)-phenyl)boronic acid with the iodoquinoline intermediate (D) in the presence of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) and 2M potassium carbonate in DMF.
  • the reaction is allowed to proceed at 85 ° C to give 7-chloro-4- ethoxy-3-(4-(trifluoromethoxy)phenyl)quinoline (E) in approximately 63% yield as white crystalline material after flash chromatography.
  • the desired compound (Compound 1 ) is obtained by reacting the 4-ethoxy quinoline derivative (E) with N- tert-butyl propane 1 ,3 diamine in the presence of phenol according to the procedure of Andersag supra, in a Ca us tube using 2 ethoxyethanol as a solvent at 180 ° C for 4 days.
  • the crude product is further purified by flash chromatography followed by crystallization in ethyl acetate to give Compound 1 as transparent white rectangular plates in approximately 59% yield.
  • 7-chloro-3-iodoquinolin-4-ol may be synthesized as follows. To a stirred suspension of 7-chloro-quinolone (A) (20.0 gm, 1 1 1 mmol) in DMF (100 ml_) is added successively n-butylamine (81 .2 gm, 1 .1 1 mol), iodine (19.8 gm, 155.6 mmol) and 20 ml_ of saturated aqueous potassium iodide (Kl). Upon the addition of n-butyl amine all of (A) dissolves. The yellow solution is stirred at room temperature for 36 hours.
  • the suspension is then suction filtered over a layer of silica gel placed inside a fritted funnel and washed with ethyl acetate (3 x 20mL).
  • the cloudy yellow solution is further filtered over celite and rotoevaporated to afford 4.64 gm (approximately 90% yield) of (D) as a white solid.
  • TLC thin layer chromatography
  • GC-MS shows one peak with 333 M+, 76%; 305 (M-Et), 100%.
  • 7-chloro-4-ethoxy-3 -(4-(trifluoromethoxy) phenyl)quinoline (E) may be synthesized as follows.
  • the solution is allowed to cool to room temperature, diluted with ethyl acetate (50 mL), suction filtered over a layer of silica gel placed on top of a thin layer of Celite, to eliminate the palladium catalyst, and washed with an additional 50 mL of ethyl acetate.
  • the combined filtrate is dried over Na2SO4, filtered and roto-evaporated to afford 529 mg of a white solid. This material is suspended in 2-3 ml of CH2CI2 and the insoluble material is filtered out through Celite.
  • the solution may be purified by flash chromatography using hexane/ethyl acetate 8/2 as eluent to give approximately 232 mg (approximately 63% yield) of (E) as a white crystalline solid.
  • GC-MS may show one peak with 367 M+, 75%; 339 (M-Et), 100%.
  • Compound 1 N1 -(tert-butyl)-N3-(7-chloro-3-(4-(trifluoromethoxy)-phenyl)- quinolin-4-yl)propane-1 ,3-diamine, may be synthesized as follows. A stirred solution of (E) (367 mg, 1 .0 mmol), N-tert butyl propane 1 ,3 diamine (390 mg, 3.0 mmol), phenol (282 mg, 3.0 mmol) and 2-ethoxy ethanol (5 mL) in a Carius tube is placed in an 180 ° C oil bath for 4 days.
  • This material may be purified by flash chromatography using (ethyl acetate/triethylamine 9/1 )/hexane 50/50 as eluent to give approximately 266 mg (approximately 59% yield) of (Compound 1 ) as a white crystalline solid.
  • This material is dissolved in ethyl acetate and the solvent is allowed to slowly evaporate in the hood to give transparent white rectangular plates. An x-ray structure of this material may be obtained to confirm its structure.
  • GC-MS may show one peak with 451 M+, 28%; 351 (M-C6H14N), 100%.
  • compound 1 can be synthesized according to Scheme 2 by performing the Suzuki coupling directly on the 4-chloro 3-iodo quinoline (C) using dichloro [1 ,1 ' bis (diphenylphosphino)ferrocene)] palladium (II) [PdCI 2 (dppf)] (Hayashi, T. J. Am. Chem. Soc. 1984, 106, 158-163, incorporated by reference herein) as a catalyst to give 4,7-dichloro-3-(4-(trifluoromethoxy)phenyl)quinoline (P) in 79% yield a white solid after flash chromatography.
  • the desired product compound 1 is obtained using the same procedure as described in Scheme 2 in approximately 90 % yield. In some embodiments, this new and more efficient method (Scheme 2) may give an overall yield of approximately 42 %.
  • 4,7-dichloro-3-(4- (trifluoromethoxy) phenyl)quinoline (P) may be synthesized as follows. 4,7-dichloro- 3-iodoquinoline (C) (3.23 gm 10.0 mmol) and 4-(4-(trifluoromethoxy)phenyl)boronic acid (2.06 gm, 10.0 mmol) is dissolved in DMF (60 ml_) while degassing with argon. To this stirred solution is added 10 mL of 2M K 2 CO 3 (20.0 mmol) resulting in a formation of a white precipitate. Next, dichloro [1 ,1 ' bis
  • the suspension is stirred vigorously for 30 minutes at room temperature, filtered through celite and rotoevaporated to afford approximately 4.10 gm of brown solid.
  • This material may be purified by flash chromatography using hexane/ethyl acetate 9/1 as eluent to give approximately 2.83 gm (approximately 79% yield) of (P) as a white solid.
  • Compound 1 Ni-(tert-butyl)-N3-(7-chloro-3-(4-(trifluoromethoxy)phenyl)- quinolin-4-yl)propane-1 ,3-diamine, may be synthesized as follows. A stirred solution of (P) (357 mg, 1 .0 mmol), N-tert butyl propane 1 ,3 diamine (390 mg, 3.0 mmol), phenol (94 mg, 1 .0 mmol) and 2-ethoxy ethanol (3 mL) in a Carius tube is placed in an 150 ° C oil bath for 24 hours. GC-MS may show no more starting material with clean formation of the desired product compound 1.
  • compositions including therapeutic and prophylactic formulations.
  • Pharmaceutical compositions as described herein include one or more compounds according to the present description.
  • pharmaceutical compositions according to the present disclosure may include one or more additional therapeutic agents, including, for example, one or more additional antimalarial or antiinfective agent, antibiotics, anti-inflammatory agents, or drugs that are used to reduce pruritus, such as an antihistamine.
  • additional therapeutic agents including, for example, one or more additional antimalarial or antiinfective agent, antibiotics, anti-inflammatory agents, or drugs that are used to reduce pruritus, such as an antihistamine.
  • the one or more compounds as described herein and, optionally, the one or more additional active agents may be combined together with one or more pharmaceutically acceptable vehicles or carriers.
  • compositions described herein may be combined with or used simultaneiously with one or more other therapeutic regimens or compositions.
  • additional antimalarial or antiinfective agent may be included in a pharmaceutical composition according to the present invention, such agent(s) may be selected from, for example, quinolines, such as chloroquine, quinine, and mefloquine; the antifolates, such as pyrimethamine and sulfadoxine; and the anti-respiratory combination of atovaquone and proguanil.
  • compositions according to the present invention may be administered to subjects by a variety of mucosal administration modes, including by oral, rectal, intranasal, intrapulmonary, or transdermal delivery, or by topical delivery to other surfaces.
  • the compositions can be administered by non-mucosal routes, including by intramuscular, subcutaneous, intravenous, intra-arterial, intraarticular, intraperitoneal, intrathecal, intracerebroventricular, or parenteral routes.
  • the compound can be administered ex vivo by direct exposure to cells, tissues or organs originating from a subject.
  • the one or more compounds may be combined with various pharmaceutically acceptable additives, as well as a base or vehicle for dispersion of the compound.
  • additives include, but are not limited to, pH control agents, such as arginine, sodium hydroxide, glycine, hydrochloric acid, and citric acid.
  • local anesthetics for example, benzyl alcohol
  • isotonizing agents for example, sodium chloride, mannitol, sorbitol
  • adsorption inhibitors for example, Tween 80 or medium chain triacylglycerols such as myglyol 812
  • solubility enhancing agents for example, cyclodextrins and derivatives thereof
  • stabilizers for example, serum albumin
  • reducing agents for example, glutathione
  • Adjuvants such as aluminum hydroxide (for example, Amphogel, Wyeth Laboratories, Madison, NJ), Freund's adjuvant, MPLTM (3-O-deacylated monophosphoryl lipid A; Corixa, Hamilton, MT) and IL-12 (Genetics Institute, Cambridge, MA), among many other suitable adjuvants well known in the art, may be included in the composition.
  • the tonicity of the formulation as measured with reference to the tonicity of 0.9% (w/v) physiological saline solution taken as unity, may be adjusted to a value at which no substantial, irreversible tissue damage will be induced at the site of administration.
  • the tonicity of the solution may be adjusted to a value of about 0.3 to about 3.0, such as about 0.5 to about 2.0, or about 0.8 to about 1 .7.
  • the one or more compounds may be dispersed in a base or vehicle, which can include a hydrophilic compound having a capacity to disperse the compound, and any additives.
  • the base may be selected from a wide range of suitable compounds, including but not limited to, copolymers of polycarboxylic acids or salts thereof; carboxylic anhydrides (for example, maleic anhydride); with other monomers (for example, methyl(meth)acrylate and acrylic acid); hydrophilic vinyl polymers, such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives such as hydroxymethylcellulose and hydroxypropylcellulose; natural polymers, such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid; and nontoxic metal salts thereof.
  • a biodegradable polymer may be selected as a base or vehicle, such as, for example, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyhydroxybutyric acid, poly(hydroxybutyric acid-glycolic acid) copolymer and mixtures thereof.
  • synthetic fatty acid esters such as polyglycerin fatty acid esters and sucrose fatty acid esters may be employed as vehicles.
  • Hydrophilic polymers and other vehicles can be used alone or in combination, and enhanced structural integrity can be imparted to the vehicle by, for example, partial crystallization, ionic bonding, or cross-linking.
  • the vehicle may be provided in a variety of forms, including fluid or viscous solutions, gels, pastes, powders, microspheres, and films for direct application to a mucosal surface.
  • the one or more compounds may be combined with the base or vehicle according to a variety of methods, and release of the compound may be via diffusion, disintegration of the vehicle, or associated formation of water channels.
  • the compound may be dispersed in microcapsules (microspheres) or nanoparticles prepared from a suitable polymer, for example, 5- isobutyl-2-cyanoacrylate (see, for example, Michael et al., J. Pharmacy Pharmacol. 43:1 -5, 1991 ), and dispersed in a biocompatible dispersing medium, which may provide sustained delivery and biological activity over a protracted time.
  • the one or more compounds may be combined with a mesoporous silica nanoparticle, such as a mesoporous silica nanoparticle complex with one or more polymers conjugated to its outer surface.
  • the pharmaceutical compositions of the disclosure may contain as pharmaceutically acceptable vehicles, substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, and wetting agents, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate.
  • substances as required to approximate physiological conditions such as pH adjusting and buffering agents, tonicity adjusting agents, and wetting agents, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate.
  • conventional nontoxic pharmaceutically acceptable vehicles may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, and magnesium carbonate.
  • compositions for administering the one or more compounds may also be formulated as a solution, microemulsion, or other ordered structure suitable for a high concentration of active ingredients.
  • the vehicle may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • polyol for example, glycerol, propylene glycol, and liquid polyethylene glycol
  • suitable mixtures thereof for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • Proper fluidity for solutions may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a desired particle size in the case of dispersible formulations, and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the one or more compounds may be obtained by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the one or more compounds may be administered in a time release formulation, for example in a composition which includes a slow release polymer.
  • a composition which includes a slow release polymer may be prepared with vehicles that will protect against rapid release, for example, a controlled release vehicle such as a polymer, microencapsulated delivery system or bioadhesive gel.
  • Controlled release binders suitable for use in accordance with the disclosure include any biocompatible controlled release material which is inert to the active agent and which is capable of incorporating the compound and/or other biologically active agent. Numerous such materials are known in the art. Controlled-release binders may be materials that are metabolized slowly under physiological conditions following their delivery (for example, at a mucosal surface, or in the presence of bodily fluids).
  • Exemplary binders include, but are not limited to, biocompatible polymers and copolymers well known in the art for use in sustained release formulations.
  • biocompatible compounds are non-toxic and inert to surrounding tissues, and do not trigger significant adverse side effects, such as nasal irritation, immune response, or inflammation. They are metabolized into metabolic products that are also biocompatible and easily eliminated from the body.
  • Exemplary polymeric materials for use in the present disclosure include, but are not limited to, polymeric matrices derived from copolymeric and homopolymeric polyesters having hydrolyzable ester linkages. A number of these are known in the art to be biodegradable and to lead to degradation products having no or low toxicity.
  • Exemplary polymers include polyglycolic acids and polylactic acids, poly(DL- lactic acid-co-glycolic acid), poly(D-lactic acid-co-glycolic acid), and poly(L-lactic acid- coglycolic acid).
  • biodegradable or bioerodable polymers include, but are not limited to, poly(epsilon-caprolactone), poly(epsilon-caprolactone-CO- lactic acid), poly(epsilon-caprolactone-CO-glycolic acid), poly(beta-hydroxy butyric acid), poly(alkyl-2-cyanoacrylate), hydrogels such as poly(hydroxyethyl methacrylate), polyamides, poly(amino acids) such as L-leucine, glutamic acid, L- aspartic acid, poly(ester urea), poly(2-hydroxyethyl DL-aspartamide), polyacetal polymers, polyorthoesters, polycarbonate, polymaleamides, polysaccharides, and copolymers thereof.
  • poly(epsilon-caprolactone) poly(epsilon-caprolactone-CO- lactic acid), poly(epsilon-caprolactone-CO-gly
  • compositions of the disclosure typically are sterile and stable under conditions of manufacture, storage and use.
  • Sterile solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization.
  • Dispersions may be prepared by incorporating the compound and/or other biologically active agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
  • methods of preparation include vacuum drying and freeze-drying which yields a powder of the compound plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.
  • the compounds and pharmaceutical compositions disclosed herein may be used for treating, inhibiting or preventing parasitic diseases, such as malaria, caused by organisms such as Plasmodium sp., including Plasmodium falciparum.
  • parasitic diseases such as malaria
  • Other examples of human or animal parasitic diseases that may be treated using the compounds and pharmaceutical compositions disclosed herein include toxoplasmosis, amebiasis, giardiasis, leishmaniasis, trypanosomiasis, coccidiosis, and schistosomiasis, caused by organisms such as Toxoplasma sp., Eimeria sp., Babesia sp, Theileria sp.
  • Additional parasites that cause malaria include Plasmodium vivax, Plasmodium ovale, Plasmodium knowlesi, Plasmodium malariae, Plasmodium yoelii, and Plasmodium berghei.
  • the compounds and compositions disclosed herein may be administered to a subject to prevent or inhibit drug-resistant malaria such as chloroquine-resistant malaria or multidrug-resistant malaria that is caused by organisms harboring resistance to chloroquine, quinine, mefloquine, pyrimethamine, dapsone, atovaquone, or any other available anti-malarial drug.
  • drug-resistant malaria such as chloroquine-resistant malaria or multidrug-resistant malaria that is caused by organisms harboring resistance to chloroquine, quinine, mefloquine, pyrimethamine, dapsone, atovaquone, or any other available anti-malarial drug.
  • the compounds and pharmaceutical compositions disclosed herein may be coadministered with another pharmaceutically active compound.
  • the compounds may be coadministered with quinine, chloroquine, atovaquone, proguanil, primaquine, amodiaquine, mefloquine, piperaquine, artemisinin, artesunate, endoperoxidases, methylene blue, pyrimethamine, sulfadoxine, artemether-lumefantrine (Coartem®), dapsone- chlorproguanil (LAPDAP®), artesunate, quinidine, clopidol, pyridine/pyridinol analogs, 4(1 H)-quinolone analogs, dihydroartemisinin, a mixture of atovaquone, proguanil, an endoperoxide, an acridone as disclosed in WO 2008/06401 1 , another 3-aryl quinoline as disclosed in
  • the compound may be delivered to a subject in a manner consistent with conventional methodologies associated with management of the disorder for which treatment or prevention is sought.
  • a prophylactically or therapeutically effective amount of the compound and/or other biologically active agent is administered to a subject in need of such treatment for a time and under conditions sufficient to prevent, inhibit, and/or ameliorate a selected disease or condition or one or more symptom(s) thereof.
  • Typical subjects intended for treatment with the compounds, compositions and methods of the present disclosure include humans, as well as non-human primates and other animals such as companion animals, livestock animals, animals used in models of parasitic infection, or animals used in pharmaceutical testing, such as pharmacokinetics and toxicological testing, including mice, rats, rabbits, and guinea pigs.
  • accepted screening methods are employed to determine risk factors associated with a parasitic infection to determine the status of an existing disease or condition in a subject. These screening methods include, for example, preparation of a blood smear from an individual suspected of having malaria.
  • the blood smear is then fixed in methanol and stained with Giemsa and examined microscopically for the presence of Plasmodium infected red blood cells.
  • the administration of the disclosed compounds and pharmaceutical compositions may be for prophylactic or therapeutic purposes.
  • the compound When provided prophylactically, the compound is administered to a subject in advance of a symptom.
  • the prophylactic administration of the compound serves to prevent or ameliorate subsequent disease process.
  • the compound When provided therapeutically, the compound is administered to a subject at or after the onset of a symptom of disease or infection.
  • the compound or pharmaceutical composition may be administered to the subject orally or in a single bolus delivery, via continuous delivery (for example, continuous transdermal, mucosal or intravenous delivery) over an extended time period, or in a repeated administration protocol (for example, by an hourly, daily or weekly, repeated administration protocol).
  • the therapeutically effective dosage of the compound may be provided as repeated doses within a prolonged prophylaxis or treatment regimen to yield clinically significant results to alleviate one or more symptoms or detectable conditions associated with a targeted disease or condition as set forth herein.
  • Suitable models in this regard include, for example, murine, rat, avian, porcine, feline, non-human primate, and other accepted animal model subjects known in the art.
  • effective dosages may be determined using in vitro models (for example, immunologic and histopathologic assays). Using such models, calculations and adjustments may be required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the compound (for example, amounts that are effective to elicit a desired immune response or alleviate one or more symptoms of a targeted disease).
  • an effective amount or effective dose of the compound may simply inhibit or enhance one or more selected biological activities correlated with a disease or condition, as set forth herein, for either therapeutic or diagnostic purposes.
  • the actual dosage of the compound may vary according to factors such as the disease indication and particular status of the subject (for example, the subject's age, size, fitness, extent of symptoms, and susceptibility factors), time and route of administration, other drugs or treatments being administered concurrently, as well as the specific pharmacology of the compound for eliciting the desired activity or biological response in the subject. Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response.
  • a therapeutically effective amount may be one in which any toxic or detrimental side effects of the compound and/or other biologically active agent is outweighed in clinical terms by therapeutically beneficial effects.
  • a non-limiting range for a therapeutically effective amount of a compound and/or other biologically active agent within the methods and compositions of the disclosure is about 0.01 mg/kg body weight to about 100 mg/kg body weight, such as about 0.05 mg/kg to about 50 mg/kg body weight, or about 0.5 mg/kg to about 5 mg/kg body weight.
  • the dosage may be varied to maintain a desired concentration at a target site (for example, the lungs or systemic circulation). Higher or lower concentrations can be selected based on the mode of delivery, for example, trans-epidermal, rectal, oral, pulmonary, or intranasal delivery versus intravenous or subcutaneous delivery. Dosage can also be adjusted based on the release rate of the administered formulation, for example, of an intrapulmonary spray versus powder or sustained release oral versus injected particulate or transdermal delivery formulations.
  • kits, packages and multi-container units containing the herein described pharmaceutical compositions, active ingredients, and/or devices and consumables that facilitate the administration the same for use in the prevention and treatment of diseases and other conditions in mammalian subjects.
  • the compound may be formulated in a pharmaceutical composition for delivery to a subject.
  • pharmaceutical compositions according to the present description may be used.
  • the compound or composition within which it is formulated may be contained in a bulk dispensing container or unit or multiunit dosage form.
  • Optional dispensers can be provided, for example, a pulmonary or intranasal spray applicator.
  • Packaging materials optionally include a label or instruction indicating for what treatment purposes and/or in what manner the pharmaceutical agent packaged therewith can be used.
  • the method of treating a Plasmodium infection comprises administering a therapeutically effective amount of a compound.
  • the compound may be administered orally, subcutaneously, intravenously, or intramuscularly to a subject suffering from or at risk of suffering from a Plasmodium infection.
  • the Plasmodium infection may be an infection with a Plasmodium strain resistant to one or more of the following classes of compounds: quinine, mefloquine, chloroquine, or atovaquone.
  • Example 1 The in vitro efficacy of Exemplary Compounds.
  • Table 1 shows the antiplasmiodial IC 50 values (nM) of several antimalarial agents, in comparison to certain compounds disclosed herein, when used against selected P. falciparum strains.
  • the D6 strain of P. falciparum is sensitive to the antiplasmodial action of chloroquine, but strains Dd2, Tm90.C2B (not shown), and 7G8 are all resistant to chloroquine and are all multidrug resistant strains.
  • the Dd2 and Tm90.C2B strains also exhibit a high level of resistance to quinine and mefloquine, while Tm90.C2B is also resistant to atovaquone.
  • Table 2 summarizes the in vitro and in vivo activities of Compound 1 .
  • Compound 1 was evaluated at 1 ⁇ , 4 ⁇ , and 12 ⁇ concentrations in duplicate with controls. Compound 1 inhibits hERG channel activity in a concentration dependent manner yielding an ICso of 4.0 ⁇ .
  • chloroquine (2.5 ⁇ ), mefloquine (2.6 ⁇ ), and halofantrine (0.04 ⁇ ) are cited as well (Traebert, et al., supra).

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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  • General Chemical & Material Sciences (AREA)
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Abstract

L'invention concerne des composés, des compositions et des procédés utiles pour le traitement de maladies infectieuses. En particulier, des composés de 3-aryl-quinoléine, leur synthèse, des compositions pharmaceutiques associées et des procédés de traitement de maladies infectieuses, telles que la malaria, sont décrits.
PCT/US2013/021472 2012-01-13 2013-01-14 Composés, compositions et procédés associés comprenant des 3-aryl-quinoléines WO2013106847A1 (fr)

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US14/371,870 US9249103B2 (en) 2012-01-13 2013-01-14 Compounds, compositions and associated methods comprising 3-aryl quinolines
EP13735565.7A EP2802565A4 (fr) 2012-01-13 2013-01-14 Composés, compositions et procédés associés comprenant des 3-aryl-quinoléines
US14/977,271 US20160340313A1 (en) 2012-01-13 2015-12-21 Compounds, compositions and associated methods comprising 3-aryl quinolines
US15/440,458 US10023538B2 (en) 2012-01-13 2017-02-23 Compounds, compositions and associated methods comprising 3-aryl quinolines

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US61/586,690 2012-01-13

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US14/977,271 Continuation US20160340313A1 (en) 2012-01-13 2015-12-21 Compounds, compositions and associated methods comprising 3-aryl quinolines

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US20160340313A1 (en) 2016-11-24
EP2802565A4 (fr) 2015-07-08
US20140350048A1 (en) 2014-11-27
EP2802565A1 (fr) 2014-11-19
US20180009760A1 (en) 2018-01-11
US9249103B2 (en) 2016-02-02

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